TBI sometimes causes severe brain damage, and it can also lead to recurrent inflammation of the brain. This ongoing inflammation can extend the damage to the brain. Only a few drugs help (anti-inflammatory drugs for example). Up to half of patients with serious TBI need surgery, but some stem cells like a sub group of mesenchymal stem cells called multipotent adult progenitor cells (MAPCs) can reduce short-term inflammation, and induce functional improvement in mice with TBI. Unfortunately, few groups have gauged the long-term effects of MAPCs on TBI.

In an article that appeared in the journal Stem Cells Translational Medicine, a research team led by the Director of the Children’s Program in Regenerative Medicine, Charles Cox, reported the use of human MAPCs in mice that had suffered TBI.

Charles Cox, Jr., MD

In this study, Cox and his colleagues infused MAPCs into the bloodstream of two groups of mice 2, and 24 hours after suffering a TBI. The first group of mice received two million cells per kilogram, and mice in the other group received an MAPC dose five times stronger.

Four months after MAPC administration, those mice that had received the stronger dose continued to experience less brain inflammation and better cognition. Spatial learning was increased and motor deficits had decreased.

According to Cox, the intravenously administered MAPCs did not cross the blood/brain barrier. Since immune cells can cross the blood/brain barrier for a short period of time after a TBI and cause autoimmunity, this result shows that the MAPCs are quelling inflammation through “paracrine” mechanisms (paracrine means that molecules are secreted by the cells and these secreted molecules elicit various responses from nearby cells). Cox made this clear: “We spent 18 months looking for them in the brain. There was little to no engraftment there.”

Rather than entering the brain, the MAPCs “set up shop in the spleen, a giant reservoir of T and B cells. The MAPCs change the spleen’s output to anti-inflammatory cells and cytokines, which communicate with immune cells in the brain—microglia—and change their response to injury from hyper-to-anti- inflammatory. The cells alter the innate immune response to injury. We have shown this in a sequence of papers.”

Microglia

University of Cambridge neurologist, Stefano Pluchino, has worked with immune regulatory stem cells. Pluchino said that Cox’s study shows a “good dose response” on disability and behavior “after hyperacute, or acute, intravenous injection of MAPCs.” However, Pluchino noted that the description of the effects of MAPCs on microglia (white blood cells in the brain that gobble up foreign matter and cell debris) is “speculative.” Pluchino continued: “It is not clear whether these counts have been done on the injured brain hemisphere, and whether MAPC effects were observable on the unaffected hemisphere. The distribution and half-life of these MAPCs is not clear” and has never been demonstrated convincingly in Athersys papers (side note: Athersys is the company that isolates and grows the human MAPCs). “It is also not clear if effects in the Cox study were a ‘false positive,’ secondary to a paradoxical immune suppression the xenograft modulates.” That is, a false positive could occur because human cells in animal bodies rouse immune reactions. “It is not clear where in the body these MAPCs would work, either out or into the injured brain.” Additionally the mechanism by which these cells act does not seem to be clear, according to Pluchino.

But, Pluchino added: “Athersys is already in clinic with MAPCs in graft vs. host disease, myocardial infarction, stroke, progressing towards a phase I/II clinical trial in multiple sclerosis, and completing the pre-clinical work in traumatic brain and spinal cord injuries. Everything looks great. The company is solid. The data is convincing in terms of behavioral and pathological analyses. But the points I have raised are far from clarified.”

Cox admitted that Pluchino’s points are valid. He pointed out that human cells were used in rodents, since the FDA wants pre-clinical studies in laboratory animals in order to first evaluate the safety and efficacy of the exact cells to be used in a proposed therapy before they head to the clinic. “As we are not seeking engraftment of these cells, and would not plan to immunosuppress a trauma patient, we have not pursued animal models that use immunosuppression. Our study was designed with translationally relevant end-points, recognizing the limitations of not having a final mechanism of action determined. The growing consensus is there are many mechanism(s) of action in cell therapies.”

Cox also agreed that the suggested effects of MAPCs on microglia, “is not truly a proof of mechanism.” However, Cox and his co-workers have developed a protocol that can potentially more accurately quantify microglia in mice. “We ultimately plan more mechanistic studies to define endogenous microglia versus infiltrating microglia and the effects of various cell therapies. “

Additionally, Cox also said that: “We have published work showing the majority of acutely infused MSCs and MAPCs are lodged in the lung after intravenous delivery. This was an acute study in non-injured animals, but others have shown similar data.” In another study, Cox’s research group showed that the cells cluster in the spleen, which corroborates work by other research groups that have used umbilical cord cells to treat stroke.

Finally, Cox disagrees that the suppression of immune cell function in animals by human cells is appropriately characterized as “a false positive.” Cox explained that the infused cells induce a “modulation of the innate immune response, and typically, the immune rejection of a transplant is associated with immune activation, not suppression. So it well may be a ‘true positive.’”

In order for MAPCs to make to the clinical trial stage, Cox will need to investigate the mechanisms by which MAPCs suppress inflammation and if their purported effects on microglia in the central nervous system are real. He will also need to show that these cells work in other types of laboratory animals beside mice. Rats will probably be next, and after that, my guess is that the FDA would allow Athersys to apply for a New Drug Application.